Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases

@article{Goodwill1997CrystalSO,
  title={Crystal structure of tyrosine hydroxylase at 2.3 {\AA} and its implications for inherited neurodegenerative diseases},
  author={Kenneth E. Goodwill and Christelle Sabatier and Cara B. Marks and Reetta Raag and Paul F. Fitzpatrick and Raymond C. Stevens},
  journal={Nature Structural Biology},
  year={1997},
  volume={4},
  pages={578-585}
}
Tyrosine hydroxylase (TyrOH) catalyzes the conversion of tyrosine to L-DOPA, the rate-limiting step in the biosynthesis of the catecholamines dopamine, adrenaline, and noradrenaline. TyrOH is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase (PheOH) and tryptophan hydroxylase (TrpOH). The crystal structure of the catalytic and tetramerization domains of TyrOH reveals a novel α-helical basket holding the catalytic iron and a 40 Å long anti… 
Structure of Tetrameric Human Phenylalanine Hydroxylase and Its Implications for Phenylketonuria*
TLDR
The crystal structure of human PheOH is determined and displays an overall architecture similar to that of the functionally related tyrosine hydroxylase, which is the first report of a tetrameric Phe OH.
Structure and Regulation of Phenylalanine Hydroxylase, and Implications for Related Enzymes
TLDR
Over 300 different mutations in the PAH gene have been found to be associated with the disease phenylketonuria (PKU), although only a small proportion of mutant proteins have been functionally characterised.
Structure–Function Relationships in the Aromatic Amino Acid Hydroxylases Enzyme Family: Evolutionary Insights
TLDR
The AAAHs have developed sophisticated regulatory mechanisms during evolution to control substrate l-Phe (PAH), catecholamine (TH), serotonin and melatonin (TPHs) levels and are highly regulated by mechanisms at the transcriptional, translational, posttranslational and allosteric levels.
Crystal structure of tryptophan hydroxylase with bound amino acid substrate.
TLDR
The 1.9 A resolution crystal structure of the catalytic domain of chicken TPH isoform 1 (TPH1) in complex with the tryptophan substrate and an iron-bound imidazole is determined, which is the first structure of any aromatic amino acid hydroxylase with bound natural amino acid substrate.
Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein
TLDR
The results establish that the physiological effects of the mutations are primarily due to the decreased stability of the mutant proteins rather than decreases in their intrinsic activities.
The solution structure of the regulatory domain of tyrosine hydroxylase.
Intersubunit binding domains within tyrosine hydroxylase and tryptophan hydroxylase
TLDR
These studies indicate that, although the proposed salt bridge dimerization interface of TH is conserved in TPH, this hypothetical TPH intersubunit binding domain, K111–E223, is not required for the proper macromolecular assembly of the protein.
The structural basis of the recognition of phenylalanine and pterin cofactors by phenylalanine hydroxylase: implications for the catalytic mechanism.
TLDR
The conformation and distances to the catalytic iron of both L-Phe and the cofactor analogue L-erythro-7,8-dihydrobiopterin (BH2) simultaneously bound to recombinant human PAH have been estimated by (1)H NMR.
Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines
TLDR
Investigation of the role of the N-terminus of TH enzyme in the regulation of both the catalytic activity and the intracellular stability will extend the spectrum of the gene-therapy approach for PD.
Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation
TLDR
The authors present the cryo-EM structures of full-length human TH in the apo form and bound with DA, as well as the structure of Ser40 phosphorylated TH, and discuss the inhibitory and stabilizing effects of DA on TH and its counteraction by Ser40-phosphorylation.
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References

SHOWING 1-10 OF 37 REFERENCES
A Carboxyl Terminal Leucine Zipper Is Required for Tyrosine Hydroxylase Tetramer Formation
TLDR
This represents the first report of the functional involvement of a region containing a leucine zipper motif in the assembly and activity of a neuronal enzyme.
Expression and characterization of catalytic and regulatory domains of rat tyrosine hydroxylase
TLDR
Results establish that all of the catalytic residues of tyrosine hydroxylase are located in the C‐terminal 330 amino acids, consistent with a model in which the C-terminal two‐thirds constitute a conserved catalytic domain to which has been appended discrete regulatory domains.
Identification of Gln313 and Pro327 as Residues Critical for Substrate Inhibition in Tyrosine Hydroxylase
TLDR
Rat tyrosine hydroxylase was expressed in Escherichia coli and the smallest fragment of tyrosines that gave a soluble active molecule was from Leu188 to Phe456, suggesting that corresponding residues in phenylalanine hydoxylase and tyrosin hydroxyase can have different roles in pterin function.
Characterization of the Active Site Iron in Tyrosine Hydroxylase
TLDR
Purification of recombinant rat tyrosine hydroxylase containing 0.5-0.7 iron atoms/subunit and lacking bound catecholamine has permitted studies of the redox states of the resting enzyme and the enzyme during catalysis, which reveals a fraction of the enzyme is oxidized during turnover.
A mechanism for hydroxylation by tyrosine hydroxylase based on partitioning of substituted phenylalanines.
TLDR
A series of 4-X-substituted phenylalanines have been characterized as substrates to gain insight into the mechanism of hydroxylation, and the total amount of product formed with each amino acid showed a very good correlation with the sigma parameter of the substituent.
Delineation of the catalytic core of phenylalanine hydroxylase and identification of glutamate 286 as a critical residue for pterin function.
TLDR
Rat phenylalanine hydroxylase was expressed in Escherichia coli and mutants identified Glu286 as an amino acid critical for pterin function in phenylAlanine hydoxylase.
Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene.
TLDR
Treatment with L-DOPA resulted in normalisation of the CSF homovanillic acid concentration and a sustained improvement in parkinsonian symptoms, and expression studies are compatible with the severe clinical phenotype of the L205P homozygous patient carrying this recessively inherited mutation.
Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene.
TLDR
The 'residual activity' of about 15% of the corresponding wild-type hTH (isoform hTH1), at substrate concentrations prevailing in vivo, is compatible with the clinical phenotype of the two Q381K homozygote patients carrying this recessively inherited mutation.
Identification of the intersubunit binding region in rat tyrosine hydroxylase.
TLDR
The carboxyl terminus is responsible for tetramer formation by tyrosine hydroxylase and the sequence of amino acids removed is consistent with a coiled coil structure in the intact tetramer.
Structure and function of the aromatic amino acid hydroxylases.
TLDR
Three aromatic amino acid hydroxylases constitute a family of enzymes that share many physical, structural and catalytic properties and are the ratelimiting step in the biosynthesis of catecholamines.
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